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Peyronie Disease

Author: Darren P. Sandean Author: Stephen W. Leslie Editor: Saran Lotfollahzadeh Updated: 10/6/2024 4:03:14 PM

Introduction

Peyronie disease is a progressive and nonmalignant disorder of the penis resulting in an abnormal curvature during erection. The condition was observed in 1561 by Gabriele Fallopius and Andreas Vesalius but was named after François Gigot de la Peyronie, the personal physician of King Louis XV and cofounder of the French Académie Royale de Chirurgie, who was the first to fully describe the disease in 1743.[1][2]

Peyronie disease is a wound-healing disorder of the tunica albuginea that results in localized fibrosis or scarring of the tunica albuginea.[3] The abnormal curvature is caused by localized scar tissue in the walls of the corpora; the exact mechanism responsible for forming this fibrotic area remains elusive.

Peyronie disease often causes significant distress to patients due to the deformity and resultant impaired appearance and function. In addition, it is associated with erectile dysfunction, which is in itself a distressing condition. 

Etiology

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Etiology

A basic understanding of the penile anatomy is required to appreciate the etiology and pathophysiology of Peyronie disease.[4][5] The penis consists of 2 erectile bodies, the corpora cavernosa, that runs along the length of the penis. During an erection, these chambers fill with blood, increasing the size and rigidity of the penis. Each corpus cavernosum has a sheath of elastic fibers, the tunica albuginea, comprising predominantly type 1 collagen fibers. The corpora cavernosa are separated by a merger of the tunica albuginea in the midline, forming a septum that attaches ventrally and dorsally along the shaft of the penis.

In Peyronie disease, a localized fibrous plaque forms in the tunica albuginea of the corpora cavernosa. This inelastic plaque changes the straight, erect penis to a more kinked or curved appearance in the direction of the involved tunical segment. The exact mechanism of plaque formation is yet to be definitively established; the most generally accepted theory is that the plaque forms as a result of some degree of penile injury or microtrauma, particularly in men who are genetically predisposed to the condition.[6][7][8][9] Endothelial-dependent systemic arterial impairment is more frequently found in patients with Peyronie disease than healthy controls.[10] The significance of these findings in the etiology of Peyronie disease is still being studied.

Although it is not possible to definitively predict who will develop Peyronie disease, it appears to be more likely in susceptible men who engage in vigorous sexual or nonsexual activities, such as certain sports, that cause penile microtrauma. Further research is needed to improve our understanding of the true pathogenesis of Peyronie disease and the role of genetic and other factors in its clinical presentation.

The known risk factors for Peyronie disease include:

Connective Tissue Disorders

Peyronie disease is commonly associated with several fibroproliferative diseases, such as Dupuytren contracture and plantar fasciitis, suggesting a significant pathophysiologic and genetic overlap between these superficial fibrosing disorders.[9][11][12][13][14][15][16] For example, in a study involving 415 men with Peyronie disease, 89 (22.1%) had Dupuytren contractures.[12] Numerous studies have linked Peyronie disease to other systemic fibrotic disorders such as idiopathic pulmonary fibrosis, Paget disease of bone, retroperitoneal fibrosis, polyfibromatosis, and systemic sclerosis (scleroderma).[17][18][19][20][21][22]

Diabetes

Men with erectile dysfunction secondary to diabetes are 4 to 5 times more likely to develop Peyronie disease compared to the general population.[23][24][25][26][27] Diabetes is believed to aggravate the fibrotic process associated with Peyronie disease, impair wound healing, decrease tunica elasticity, worsen nociception, and increase connective tissue collagenization.[27] Better glycemic control tends to improve symptoms of Peyronie disease.[27] Diabetic patients who have surgery for Peyronie disease are less likely to develop a recurrence of their penile curvature but are more likely to have postoperative erectile dysfunction.[27] These patients are also more likely to develop an infection after a penile prosthesis implant.[27]

Family History

The genetic factors contributing to Peyronie disease are complex.[7] Evidence suggests a genetic link; the exact mechanism or responsible genes remain undetermined. The literature suggests that multiple genes, including HLA-B7, could be involved, which confer increased susceptibility to developing Peyronie disease.[6][7][9][28][29] Up to 4% of first-degree relatives develop the condition.[6][29][30][31]

Hypogonadism

Androgens play an essential role in wound healing by modulating the matrix metalloproteinases.[32] In male hypogonadism, this normal healing process is disrupted, potentially increasing the risk of Peyronie disease. Although hypogonadism may increase the risk of developing Peyronie disease and the severity of the disorder, this link remains uncertain due to conflicting study results.

In a study, 74.4% of male hypogonadal patients, defined as a serum testosterone levels <300 ng/dL, were found to have Peyronie disease.[33] The degree of curvature was higher in the hypogonadal group compared to men with Peyronie disease and normal testosterone levels.[33] This effect was also found in several other studies but refuted in others, leaving it an unresolved, open question that requires further research.[4][34][35]

Penile Injury and Prior Urological Surgery

Previous injury to the penis is a strong predictor of developing Peyronie disease. Genital or perineal trauma and iatrogenic injury, including urethral catheterization, cystoscopy, and transurethral surgery, are all linked to an increased risk of Peyronie disease.[30][36] A study involving 1011 patients reported that 15.9% of patients undergoing radical prostatectomy developed Peyronie disease.[37] In patients with no known history of trauma or surgery, repeated asymptomatic microtrauma from sexual activity may be involved when no other etiology can be determined.

Smoking and Alcohol

There is some evidence to suggest that smoking is related to Peyronie disease, although the correlation between the amount of smoking and risk is unclear. Similarly, the literature remains divisive concerning alcohol, with conflicting studies. A study by Bjekic suggests a strong correlation, but a larger-scale report by La Pera et al disproves any such relationship.[36][38]

Other risk factors include age, hyperlipidemia, erectile dysfunction, obesity, penile trauma during intercourse, and psychological disorders.[36][39][40][41] Erectile dysfunction is found in about 40% (30% to 60%) of all patients with Peyronie disease, especially in patients older than 40.[42][43][44][45][46]

Epidemiology

The reported prevalence of Peyronie disease ranges from 0.3% to 20.3%.[47] There is considerable variability by country, cohort, age, and ethnicity of patients included in the studies. Some of the variability stems from studies using different diagnostic criteria or data collection methods, such as inconsistent patient or physician reporting strategies.

For example, Lindsay and associates reported a 0.39% prevalence rate when studying a group in the United States.[48] In contrast, Schwarzer et al reported a 3.2% prevalence after mailing a standardized questionnaire to 8000 men in France.[49] A much larger three-phase study investigated the prevalence of Peyronie disease in 11420 males in the United States and reported rates of up to 13%.[50] 

White men have the highest reported incidence, but this may merely reflect the increased difficulty in obtaining information from other groups. Men aged 50 to 59 are most commonly affected by Peyronie disease, with an average age of 55 at the time of presentation.[39][42][48][51][52] However, Peyronie disease can still be present at any age in adulthood, with some reports in teenagers.[42][53] When Peyronie disease is found in younger men, it is associated with an increased number of plaques, and the patients are more likely to have elevated levels of HbA1c compared to older patients.[53]

Accurately determining the prevalence of Peyronie disease is challenging due to the embarrassment many patients feel about the condition.[54] The actual prevalence is, therefore, most likely much greater than reported and has been estimated to be as high as 18%.[2][23][54][55][56] Given the wide variation of reported prevalence rates, the best overall estimate of Peyronie disease is about 9% to 10% of adult males.[2][57][58][59]

Pathophysiology

The hallmark of Peyronie disease is the localized fibrosis of the tunica albuginea of the corpora cavernosum, leading to plaque formation and loss of elasticity, which results in the characteristic penile curvature. The tunica albuginea comprises scattered type 1 collagen strands and an irregular network of elastic fibers.

Repetitive minor trauma to the penis causing tunical mechanical stress and microvascular injury are the major contributory factors.[2][60] When the penis is squeezed or bent, such as during vigorous sexual activity, buckling forces result in overstretching and eventual delamination of the tunica albuginea fibers where the septum attaches.

This trauma damages the microvasculature, resulting in blood extravasation, fibrin deposition, and a subsequent inflammatory cascade, including fibrin trapping, extravascular infiltrate and protein accumulations, overexpression of cytokines, infiltration by macrophages, and the release of elastase, which converts the collagen in the tunica from type 1 to the more fibrous and type III.[60][61][62][63][64][65][66][67][68][69][70][71]

Coital trauma may lead to dorsal and ventral delamination of the tunica albuginea, resulting in fibrin deposition between the tunical layers and localized induration with inflammation.[3] When fibrin is not rapidly cleared from the relatively avascular tunica albuginea, various antifibrinolysis and fibrosis-promoting chemical factors are released, such as plasminogen activator inhibitor type 1 (PAI-1), transforming growth factor-beta 1 (TGF- ß1), platelet-derived growth factor (PDGF), interleukin-1 (IL-1), and IL-6.[62][65][67][69][72][73][74][75] Abnormal fibrin has been found in 95% of Peyronie plaques and none in control samples.[61] Extravasated blood and cellular infiltrates result in prolonged inflammation, edema, and sensitized nerve endings, which may be the source of the pain associated with acute phase disease.[65][67][68][69]

Wound healing is delayed and becomes unregulated due to the prolonged inflammation. The enhancement of fibrous tissue production is mediated by TGF-ß1, PAI-1, PDGF, IL-1, and IL-6.[65][67][69][72] Abnormal inflammation and wound healing are believed to be responsible for the increased cellularity around the tunica, which results in a perivascular lymphocytic infiltrate around or within the tunica itself.[76][77][78][79][80][81]

Collagen deposition is enhanced by prolonged inflammation, the increased migration of fibroblasts to the affected area, and the proliferation of myofibroblasts from increased TGF-ß1 activity.[69] Extracellular matrix proliferation from TGF-ß1 and myofibroblast activity and the effect of matrix metalloproteinase inhibition block the dissolution of fibrin and excess collagen, further promoting fibrosis.[69][72][82] The prolonged inflammation activates nuclear factor-kappa beta (NF-κB), which releases additional inflammatory cytokines, further prolonging and extending the process.[83] 

These effects collectively result in an inflammatory cascade that promotes localized fibrosis and plaque formation over normal wound consolidation.[69] This mechanism also explains why Peyronies disease occurs following penile trauma, but many patients do not recall any history of significant penile injury.

Other theories have been suggested to explain the formation of the plaques, including microtrauma, microvasculature injury, chromosomal instability of fibroblasts involved in plaque formation, aberrations in the inducible nitric oxide pathways, and patient HLA subtype.[5][84][85] Additional factors involved are the presence of cytomegalovirus within the tunica, chromosomal instability in tunica-derived fibroblasts, cytokine overexpression, increased reactive oxygen production, and a high incidence of homozygous nucleotide polymorphisms involving the TGF-β1 gene.[64][65][86][87][88][89] There is evidence that crosstalk may be involved between TGF-β, WNT/β-catenin, Hedgehog, YAP/TAZ, MAPK, ROCK, and PI3K/AKT signaling pathways.[90] Plaque calcification, primarily composed of calcium phosphate, occurs due to increased TGF-ß1 activity, which enhances osteogenesis and upregulates pleiotrophin, an osteogenic growth factor that stimulates fibroblast and osteoblast activity.[69][91][92]

Histopathology

The tunica albuginea normally contains 2 layers of elastic fibers with a collagen layer in between.[93] The outer layer is longitudinally oriented with an inner circular layer.[93] The fibrosis in Peyronie disease begins with the merging of inner septal fibers of the tunica albuginea. The plaque is composed of disorganized collagen type I and type III fibers in dense clumps together with decreased, disordered, fragmented elastin fibers.[61][64][76][93][94]

History and Physical

A small cohort study in the 1970s suggested that most patients with symptomatic Peyronie disease and curvatures experience spontaneous resolution.[95] However, this has since been refuted in many studies that indicate a spontaneous resolution rate of about 12%, with most patients seeing either no change or worsening of their condition.[25][96][97] Patients should be counseled that their condition is unlikely to resolve without medical treatment, and a considerable number of men experience worsening symptoms over time. In general, only curvatures >30° are likely to interfere with sexual activity.

There are 2 clinical phases in Peyronie disease—acute and chronic, which are poorly defined.[98] 

The acute phase typically lasts from 3 to 18 months. During this period, the penile deformity generally progresses, the characteristic plaques form, and pain with erections is commonly reported.[51][53] The hallmark finding during the active phase has classically been pain, usually with erections, but the reliability of this traditional symptom has recently been questioned.[99] The lack of progression and stability of symptoms appears to be a more reliable indicator and predictor of disease progression.[99] Treatment during the acute phase is generally conservative, with nonsteroidal anti-inflammatory drug, penile traction, vacuum erection devices, and various oral agents.

The chronic phase is characterized by a plateau of symptoms during which the disorder and any penile deformity are stable for at least 3 months, along with the resolution of any pain. The presence or absence of pain has been one of the more useful distinguishing characteristics between the 2 phases of the disease but is not necessarily a reliable indicator.[51] The development of calcifications in the plaque is a good indicator of lesional stability and a chronic phase of the disease. The chronic phase is when more aggressive treatment, such as intralesional injections or surgery, is utilized. 

History

Obtaining a detailed history and performing a thorough physical examination is crucial for accurately diagnosing Peyronie disease. This condition can be a delicate and distressing topic for patients as the ramifications on a man's sex life and relationships can be profound. Consequently, clinicians should be empathetic, delicate, professional, and understanding when evaluating patients' symptoms and eliciting their ideas, concerns, and expectations of their condition.

The psychosocial impact of the condition may warrant input from counselors and therapists as significant depression, emotional difficulties, and serious relationship issues are common and found in more than half of all Peyronie patients.[100][101][102][103] The impact on the female partner should also be evaluated.[104][105][106]

A comprehensive history should include a detailed presenting complaint and past medical, surgical, and family history, as there is a genetic heritable predisposition to develop Peyronie disease (4%). The sexual history is also particularly relevant in Peyronie disease. Patients typically present for evaluation 6 months after the first appearance of symptoms.[23][107] Penile curvature is the most common presenting symptom, followed by pain and plaque formation.[107]

Key elements to consider when taking a history of a patient with Peyronie disease include:

  • Timing: Onset and progression of symptoms. Is the patient in the acute or chronic phase?
  • Deformity: How would the patient describe the penile deformity? What is the direction and degree of curvature? Is there an hourglass deformity, hinge effect, or any other concerning abnormality?
  • Duration: How long have the symptoms been stable?
  • Erection: The degree of rigidity, ability to sustain and maintain an erection, and presence of nocturnal erections. Peyronie disease is often associated with erectile dysfunction.
  • Pain: If pain is present, is it associated with the flaccid or erect state? Both?
  • Trauma: Any history of penile trauma or fracture, urologic procedures, or surgeries?
  • Family history: Is there any family history of Peyronie or Dupuytren disease? Approximately 21% of Peyronie patients also have Dupuytren contractures.[30]
  • Medical or Surgical history: Diabetes, hypertension, and cardiovascular disease.
  • Social history: Sexual history, smoking, and recreational drug use.
  • Psychosocial factors: The condition's impact on the patient's mood, relationships, and self-esteem should be evaluated. The effect on his sexual partner should also be determined.

Examination

Accurate evaluation of penile deformity is critical for determining a baseline and planning treatment. The penis should be examined in flaccid and erect states to provide a clearer understanding of the extent of the deformity and corroboration with the patient's experience.

Examination in the erect state can be performed after intracavernosal injection of vasoactive substances as recommended by the American Urology Association guidelines.[60][108] In addition to the length of the penis, the presence of a plaque, and the degree of curvature, attention should be paid to any indentations in the corpora, the presence of an hourglass or bottleneck deformity, and any instability or buckling of the penis with a full erection when placed under bending or axial pressure.[51] The plaque is most often located dorsally but may occur in any location.[109] Such an examination is recommended before consideration of any invasive therapy. Photographs from home may be helpful but are rarely sufficient.

As a general rule, a curvature of 20° or less is considered essentially normal, 30° is considered functionally straight and usable, and 60° or more is probably sexually unusable and may ultimately require surgery. The median penile curvature noted in patients in most studies of Peyronie disease is 48°.[60]

An examination following intracavernosal injections is superior to photographs or vacuum erectile device-assisted erections for accurately determining the type and degree of the Peyronie deformity.[51][60][110] An objective assessment of the degree of curvature is essential for monitoring the disease and evaluating treatment progress, as patient estimates are notoriously unreliable.[111][112] More than half of patients tend to overestimate their curvature, and only about 20% are reasonably close.[111] Even photographs from home are not always helpful, as the erections pictured are often less than fully rigid and at odd angles. For this reason, obtaining an objective measurement, showing it to the patient, and documenting it in the medical record before starting any invasive therapy is recommended.

The stretched penile length is performed with the penis in the flaccid state. The penis is grasped at the glans and pulled gently at 90° from the body, then the length is measured and recorded.

Peyronie disease is a clinical diagnosis; laboratory testing has a limited role except when hypogonadism is suspected. In light of the strong correlation with other diseases, no workup is complete without screening the patient for comorbidities, including diabetes, cardiovascular disease, and other fibroproliferative conditions such as Dupuytren disease, plantar fasciitis, Ledderhose disease (plantar fibromatosis), and scleroderma, among others.

Evaluation

The most critical components of the evaluation are the patient's history and a thorough physical examination. There is no mandatory or necessary laboratory or imaging testing to complete a Peyronie disease workup. A testosterone level is not required unless indicated for other reasons. However, it is reasonable and advisable to screen for associated conditions, such as connective tissue disorders like Dupuytren disease or diabetes.

The American Urological Association (AUA), Canadian Urological Association (CUA), and the European Association of Urology (EAU) guidelines recommend performing an in-office intracavernous injection (ICI) test with or without penile Doppler duplex ultrasound before any invasive intervention.[60][113][114] A complete duplex ultrasound provides certain advantages, including identifying any calcifications, checking penile vascular flow, and evaluating the patient's erection quality after ICI. Penile Doppler duplex ultrasound may help locate plaques that are not easily palpated and identify internal calcifications.[115] This technique may also be helpful in cases where the diagnosis is uncertain.[115]

Levine et al recently published a calcification grading system. The investigators found that patients with grade 3 or more extensive calcifications (greater than 1.5 cm in any dimension or multiple plaques greater than 1.0 cm) were more likely to undergo surgery when they had satisfactory erectile function.[116] Patients with less severe calcifications of grade 1 (<0.3 cm) or grade 2 (0.3 to 1.5 cm) or no calcifications had no evidence of any increased likelihood to proceed with surgery.[116] 

Thin-section, high-resolution T2 magnetic resonance imaging (MRI) without fat suppression has also been shown to be an excellent imaging modality for assessing penile pathology, including Peyronie disease.[115][117][118] Plaques appear as low-signal intensity areas of the thickened tunica albuginea, but calcifications are poorly appreciated.[118] Due to the high cost and limited availability, the utility of MRI in the routine workup for Peyronie disease is unclear, and it is not currently recommended for routine use.[119]

Experimentally, penile scintigraphy with technetium Tc 99m human immunoglobulin G was able to differentiate acute-phase Peyronie disease from chronic lesions.[120]

Proposed Peyonie Disease Clinical Classification System

Trost, Mulhall, and Hellstrom have proposed a useful evidence-based clinical classification system for Peyronie disease and penile curvature that extends beyond the traditional acute and chronic phases.[99] This system, called the PTNM classification, encompasses 4 elements—Peyronie disease (P), Trauma (T), Non-Peyronie components (N, which includes congenital or maturational issues), and Mode (M, referring to active vs. chronic phases).[99]

Pain is often used to help differentiate the acute and chronic phases of Peyronie disease. However, in developing the PTNM classification system, it was found that pain did not reliably coincide with disease progression.[99]

The classification system categorizes Peyronie disease into four subtypes based on its clinical characteristics—classical, calcifying, relapsing or remitting, and progressive.[99] 

Calcifying Peyronie disease: This disease is characterized by moderate-to-severe (>1 cm) plaque calcification. Patients with this disease are more likely than average to experience disease progression, pain, and indentations or hourglass deformities. After 1 year, three-fourths of these patients develop clinically stable disease. Stable calcifying disease is defined as at least 12 months since the original presentation of the disease and no significant clinical changes in curvature, symptoms, or penile deformities for the last 3 months or a continuous period of clinical stability of at least 6 months.

Progressive disease: This disease includes cases in which patients report a noticeable worsening of their symptoms at or beyond 3 months from their initial presentation. Disease stability at 3 months suggests that the patient does not have the progressive subtype. Patients with this subtype often exhibit more severe penile curvatures, shorter periods of relative stability, higher rates of more severe penile shaft indentations, hourglass deformities, loss of penile length, calcification, and discomfort. Stability develops in three-quarters of progressive disease patients after 14 months. Stable, progressive disease is defined as at least 12 months since the original presentation of the disease and no significant clinical changes in curvature, symptoms, or penile deformities for the last 3 months or a continuous period of clinical stability of at least 6 months.

Relapsing or remitting Peyronie disease: This disease describes cases where the disorder appears to reactivate an initial period of stability of at least 6 months. Patients with shorter stable periods likely have progressive disease. Men with relapsing or remitting disease tend to be younger and experience pain for a more extended period, with relatively low rates of penile indentations or hourglass deformities. This subtype accounts for about 12% of all Peyronie disease patients. Most (75%) develop stable disease after 12 months. Stable relapsing or remitting disease is defined as at least 1 year since the original disease presentation and no significant clinical changes in curvature, symptoms, or penile deformities for the last 3 months or a continuous period of clinical stability of at least 6 months.

Classical disease: This disease is essentially a diagnosis of exclusion for men who do not meet the criteria for one of the other subtypes. These men tend to be somewhat older, have a higher percentage of chronic disease, are more likely to use phosphodiesterase type 5 inhibitors, and have spontaneous regression while being less likely to experience pain or loss of penile length than the other subtypes of Peyronie disease. About 75% become clinically stable after 2 months. Classical Peyronie disease is considered stable after 3 months or more without any significant changes in symptoms, curvature, or penile deformities.

Non-Peyronie Penile Curvatures

Non-Peyronie penile curvatures are classified into three categories—congenital, maturational, or traumatic.[99]

Congenital or maturational curvature: This category refers to patients with the disorder from birth, such as chordee, and those where it developed later, usually at puberty or somewhat later. The degree of curvature is typically lateral and <20°.

Traumatic curvature: This type can be challenging to distinguish from trauma-induced Peyronie disease. Patients with traumatic curvature are more likely to recall a specific traumatic event, have a loss of penile length, report discomfort, and enjoy a higher rate of intercourse.

Changes in curvature, symptoms, or deformities 3 months or more after disease onset suggest the progressive subtype. The presence of calcified plaques indicates the calcifying subtype. In the absence of these features, the patient is classified with classical Peyronie disease. If the disease reactivates after at least 6 months of stability, it is considered relapsing or remitting.

This classification can be easily applied with a simple ultrasound (to detect calcification) and four basic questions that are typically asked by clinicians of newly diagnosed Peyronie patients: [99]

  • When did the symptoms begin (how long have the symptoms been present?)
  • How long has the condition remained stable or unchanged?
  • Did the problem get worse after it was first presented?
  • Was there any prior disease or trauma? 

This proposed classification system appears reasonable, well-documented, and clinically useful for future research, but it is still just a proposal and requires external validation. This system was developed at a high-volume referral center and used retrospective surveys and subjective questionnaires, potentially introducing bias. Currently, the proposed classification system does not alter therapy. However, it does help explain the noted variability in the reported duration of the active phase of Peyronie disease.

Treatment / Management

Clinicians should assess and treat men with Peyronie disease only when they have the experience and diagnostic tools to evaluate, appropriately counsel, and treat the condition.[60] Clinicians should then discuss all treatment options available and the known benefits and risks or burdens associated with each treatment.[60] For some patients, comprehensive counseling regarding the nature of Peyronie disease and the typical disease course may be sufficient to alleviate concerns. There is no agreed-upon minimum curvature necessary before intervention is justified, although invasive therapy for curvatures of less than 30° is unusual. If the patient is unable to have intercourse due to Peyronie disease and has failed medical therapy, this is generally considered sufficient. 

The patient's distress over his symptoms, level of concern, and willingness to undergo various types of treatment should be fully considered in the decision-making process, in addition to any objective measures of curvature and erectile function. Patients should be provided reasonable expectations of outcomes from the various available treatments. Patients should be offered psychological support and counseling as appropriate.[114][121](B3)

Iontophoresis, also known as electromotive drug administration, uses an electrical current to enhance the transdermal absorption of topically applied medications. Many studies suggest a potential benefit, particularly for pain management; however, they involve fewer than 100 patients and lack a placebo control arm.[60][122][123][124][125][126][127][128][129][130][131][132] The AUA, CUA, and International Consortium on Sexual Medicine (ICSM) guidelines do not recommend iontophoresis in Peyronie disease due to insufficient evidence, although the treatment is promising.[60][113][114][123][133](A1)

Radiation therapy was previously used for Peyronie disease, mainly for pain control, but is no longer recommended due to adverse effects, the lack of any proven benefit, and the availability of other treatments.[60][114][134][135][136][137] When used, a limited dosage was administered and given only during the acute phase.(B3)

Nonsurgical Treatment

Various oral, mechanical, and injectable therapies are used in the nonsurgical treatment of Peyronie disease. Oral therapy, vacuum erection devices, and penile traction may be used in the early, acute phase of the disease and later in the chronic phase. Intralesional therapy is generally limited to the chronic phase when the lesion is stable.[60] 

However, very few of these therapies are supported by well-designed, double-blind, placebo-controlled, randomized trials. Obstacles to having good literature to support nonsurgical treatments include the low number of patients enrolled in studies (resulting in low statistical significance), wide heterogeneity of treatments, inadequate randomization, failure to include placebo control groups, lack of objective pre and post-treatment measurements, variable or unstated durations of follow-up, and inconsistent or undefined endpoints.[60][69][138][139][140][141][142](B3)

As a result, the evidence supporting many oral and nonsurgical treatments is insufficient, as existing trials generally have poor methodological quality and are inconclusive.[60][143] Some of the other methodological problems in published studies include: [144](A1)

  • Failure to use intracavernosal injection therapy to maximize the erection to measure the curvature reliably.
  • Measurements of plaque size are generally inaccurate except for MRI studies, which are rarely performed in Peyronie disease studies.
  • Penile pain is self-limiting, making it an unreliable indicator of disease progression.
  • The relationship between erectile dysfunction and Peyronie disease is complex to measure objectively or quantify.
  • Patient satisfaction, arguably the most useful outcome statistic, is rarely addressed or reported. 

Oral therapy: Oral therapy is highly desired by patients, but there are insufficient high-quality, adequately controlled, randomized studies to justify the routine use of any oral treatment for Peyronie disease. Most studies are small, short in duration, lack control groups, and use non-standardized treatment protocols. All such oral therapy use is off-label. Patients who demand oral treatment should be fully informed of the lack of sufficient credible evidence of efficacy.

Clinicians may offer nonsteroidal anti-inflammatory agents to help manage pain, but beyond that, there are no unapproved clinical alternative therapies that have conclusively demonstrated efficacy compared to placebo.[139][145] Despite this, many patients are desperate for nonsurgical therapies, which puts significant pressure on clinicians to provide treatments, even if there is little evidence to support any real benefit.(A1)

Current AUA and CUA guidelines do not recommend oral therapy with vitamin E, tamoxifen, procarbazine, omega-3 fatty acids, or a combination of vitamin E with L-carnitine due to a lack of documented efficacy or proven ineffectiveness.[60][114][146][147][148][149][150][151] Studies have examined all of these potential medications, with some showing promising results, although the majority are non-randomized, low-volume, and uncontrolled case studies.(A1)

A few of the most popular and promising oral agents for Peyronie disease are briefly discussed below.

  • Antioxidant monotherapy: Antioxidant monotherapy has not been shown to offer any significant benefit and is not recommended by the AUA guidelines.[60] However, a combination of antioxidants and other nonsurgical therapies has shown some efficacy in treating Peyronie disease, with the complete disappearance of the plaques reported in a few cases.[69][152][153] The antioxidants used include silymarin, propolis, bilberry, vitamin E,  silymarin, and Ginkgo biloba, but the optimal combination, duration, and dosages have not been determined.[69] Although promising, the available data on antioxidant therapy is extremely limited, with a serious lack of placebo-controlled trials limiting more widespread use.[69]
    • (B3)
  • Coenzyme Q10: Coenzyme Q10 is a fat-soluble biochemical cofactor and antioxidant. There are only minimal studies on its use in Peyronie disease, but it appears to give good results with minimal adverse effects.[154][155] A dose of 300 mg has been suggested.[155][156] The AUA guidelines do not recommend coenzyme Q10 due to insufficient evidence, but the CUA has suggested that it might be offered as a reasonable treatment option.[60][114][157] Please see StatPearls' companion resource, "Coenzyme Q10," for more information.[156]
    • (A1)
  • Colchicine: Colchicine upregulates collagenase activity while inhibiting collagen deposition and fibrosis.[140][158] Uncontrolled studies have indicated a benefit in about one-third of patients, but a randomized, double-blind placebo-controlled study showed no benefit compared to placebo.[159][160][161][162][163] Many patients do not tolerate colchicine due to gastrointestinal adverse effects.[164] The CUA guidelines state that despite the limited evidence available, colchicine may be considered for clinical use.[114] Please see StatPearls' companion resource, "Colchicine," for more information.[165]
    • (A1)
  • Pentoxifylline: Pentoxifylline reduces inflammation by blocking TGF-ß1, which interferes with collagen type I production.[87][166][167][168] A single randomized controlled trial showed significant improvement in penile curvature by 23° in 33% of patients, and a small retrospective study (without a control group) showed significant improvement in plaque size and penile curvature, but further studies and additional confirmation are required before pentoxifylline therapy can be routinely recommended.[60][140][166][169][170][171][172][173] There is some evidence that it may be helpful in multimodal combination therapy.[171][174] The typical dosage is 400 mg 3 times daily.[168] The CUA guidelines indicate that pentoxifylline may be considered for therapeutic use despite the limited data available on its effectiveness.[114] Please see StatPearls' companion resource, "Pentoxifylline," for more information.[168]
    • (B2)
  • Phosphodiesterase type 5 inhibitors: There is preliminary evidence that daily tadalafil (5 mg) may significantly slow the progression rate of penile curvature in patients with Peyronie disease if started early.[175][176][177][178][179][180][181] Phosphodiesterase type 5 inhibitors inhibit collagen deposition by blocking cyclic GMP degradation and reducing pain.[140][176][178][182][183][184] 
    • The rationale for their use is that by increasing and preserving cyclic GMP, phosphodiesterase type 5 inhibitors stimulate nitric oxide production and block collagen synthesis while inducing fibroblast apoptosis and reducing myofibroblastic differentiation.[182][184][185] 
    • Combination therapy with C histolyticum collagenase intralesional injections has been shown to improve outcomes.[180]
    • Experimental in vitro studies suggest a synergistic relationship between phosphodiesterase type 5 inhibitors and statins in slowing the transformation of tunica albuginea fibroblasts into myofibroblasts, thereby reducing the progression of fibrosis in Peyronie disease.[186]
    • Although promising, there are no published, double-blinded, large-scale, placebo-controlled trials to support the routine use of phosphodiesterase type 5 inhibitors for Peyronie disease. However, the European Urology Association guidelines permit their use in all phases of the disease, and patients may experience benefits, particularly for associated erectile dysfunction.[140]
    • (A1)
  • Potassium para-aminobenzoate: Also known as potaba. This drug is believed to have anti-fibrosis and anti-inflammatory properties and has been shown to inhibit collagen formation in vitro. Potassium para-aminobenzoate may be useful in patients with a curvature of 30° or less, but there is no clear evidence of any significant benefit otherwise. Randomized studies show no improvement over placebo.[112][140][149][150][187] The treatment involves a very large number of tablets, totaling 12 g, taken 4 to 6 times a day, which causes significant gastrointestinal adverse effects that are not easily tolerated by the majority of patients. Potassium para-aminobenzoate is not recommended by the AUA or ICSM but is allowed by the CUA and the EAU based on 2 studies suggesting efficacy.[60][113][114][133][149][174]
    • (A1)
  • Vitamin E: Vitamin E is possibly the most frequently recommended oral agent for Peyronie disease due to its ability to reduce free radical activity and oxidative stress in wounds.[140][188] However, no studies have shown any significant clinical benefit from vitamin E in Peyronie disease, including a recent meta-analysis and a randomized controlled trial.[146][151][189] Therefore, the current AUA guidelines, the ICSM, the EAU, the CUA, and the AUA Core Curriculum on Peyronie disease do not recommend its use.[60][113][114][133][174] Please see StatPearls' companion resource, "Vitamin E," for more information.[190]
    • (A1)

Extracorporeal shockwave therapy: This therapy is effective in relieving pain but has consistently failed to demonstrate any benefit in penile length, curvature, or deformity in a number of studies.[175][191][192][193][194][195][196][197][198][199][200] The treatment disrupts Peyronie plaques directly, causing subsequent tissue remodeling.[113] Extracorporeal shockwave therapy may also increase vascularity in the tunica from a localized inflammatory reaction, which upregulates macrophage activity, resulting in the reabsorption of plaque calcifications.[113] Extracorporeal shockwave therapy appears effective in treating pain but has no significant clinical impact on penile curvature or plaque size.[191][198][201][202][203] The addition of daily tadalafil (5 mg) can help patients with Peyronie disease who also have erectile dysfunction.[175](A1)

Extracorporeal shockwave therapy is allowed for pain control under the AUA guidelines, which give it only a weak, conditional recommendation.[60] The reason for this modest recommendation is that there are other treatments available to treat penile discomfort; the pain is self-limiting and disappears without treatment over time, and obtaining extracorporeal shockwave therapy may be difficult and costly.[60] There are also concerns about possible adverse effects such as increased delayed scarring and erectile dysfunction.[204] Extracorporeal shockwave therapy is approved only for pain control by the CUA, EAU, and ICSM guidelines.[113][114][133][174](B3)

Intralesional injection therapy: Intralesional injection therapy is a viable nonoperative option for the treatment of Peyronie disease and is generally the next step in treatment when simpler oral and manipulative (traction) therapies fail. However, it is typically ineffective if the plaques are calcified, if there is a significant loss of penile volume, for hourglass deformities, penile shaft indentations, or if the curvature is >90°.[205] All intralesional injections are used only in the stable or chronic phase of Peyronie disease, with a few exceptions as noted.[140] 

This therapy is typically combined with careful manual manipulation and modeling by the clinician and patient to reduce the penile curvature.[60] Intralesional injection therapy is generally recommended in patients with a curvature between 30° and 90° who have intact erectile function.[60] This therapy is also suggested for patients who do not want surgery and where less invasive therapies have been ineffective or are otherwise unsuitable. Patients with penile shaft indentations, hinge effect, hourglass deformities, and curve improvements after treatment of <15° are unlikely to be satisfied with intralesional therapy and ultimately are likely to undergo surgery.[206]

  • Dexamethasone is a widely used steroidal anti-inflammatory and immunosuppressive agent.[207][208] A double-blinded randomized trial failed to show any benefit from intralesional dexamethasone injections regarding penile curvature or plaque size.[209] However, this study only included patients with chronic disease and excluded those in the acute phase where, arguably, anti-inflammatory treatment with dexamethasone injections might have been more effective.[139][209] 
    • (B3)
  • Methylprednisolone is another steroid-based anti-inflammatory drug frequently used for arthritis, asthma, and allergic reactions.[210] In a prospective single-arm nonrandomized study, 48 patients with acute phase Peyronie disease were treated with low-dose methylprednisolone intralesional injections.[211] Plaque size and other symptoms of Peyronie disease improved, and there were no adverse effects. Neither dexamethasone nor methylprednisolone intralesional injections are recommended by the AUA, CUA, or the EAU guidelines.[60][114][139]
    • (A1)

The AUA guidelines state that clinicians may offer intralesional injection therapy with C histolyticum collagenase, interferon-alpha-2b, or verapamil. However, only the collagenase is approved by the Food and Drug Administration (FDA) for treating Peyronie disease.[60] Local anesthesia with a penile block is recommended for pain control before treatment.

C histolyticum collagenase intralesional injections: These injections are the only FDA-approved therapy for treating Peyronie disease.[60][114][212] Collagenase has demonstrated the ability to dissolve excess fibrous tissue enzymatically.[213] Collagenase was approved by the FDA in December 2013 and has also been approved by the CUA, EAU, Health Canada, and ICSM.[60][113][114][133][174](A1)

Before starting treatment, a detailed discussion with the patient is required regarding possible adverse outcomes and risks, including penile bruising, swelling, pain, failure of the treatment, and corporal rupture.[60] Fortunately, penile fractures and corporal ruptures are pretty rare, with a relative risk of <1% in large series.[214] These ruptures occur within 2 weeks of the collagenase injection and are associated with morning (nocturnal) erections and sexual intercourse.[214] Four weeks of sexual abstinence is recommended after each therapy cycle to minimize the risk of injury. The recommended standard technique is described below: [141](B3)

  • The collagenase (0.58 mg) is injected laterally, from side to side, through the fibrous plaque where the curvature is most acute. Each therapy cycle includes 2 separate injection treatment sessions performed 1 to 3 days apart. Several days after the second injection of each therapy cycle, the clinician performs manual molding, bending, and modeling.
  • The patient is then instructed to do daily modeling at home for the next 6 weeks, after which he is ready for the next therapy cycle of 2 more injection sessions. Four complete therapy cycles, performed 6 weeks apart, are recommended for 24 weeks. 
  • Collagenase injections should be used cautiously in dorsal plaques and not used for ventral lesions due to the potential for damage to critical underlying structures.[215] Calcified plaques respond less effectively compared to pure fibrous lesions without calcifications, although there have been a few successful cases reported.[216][217]

A 2021 study involving 296 patients with Peyronie disease showed that two-thirds of the men who did not achieve at least a 10° (or 20%) improvement in their penile curvature after the first 2 therapy cycles could meet this threshold after completing the final 2 treatments.[218] Patients who fail an entire course of therapy with C histolyticum collagenase intralesional injections might benefit from repeating it.[219] No additional benefit has been noted with additional therapy if the first 2 complete protocols were not successful.[219] (B2)

Modified shortened protocols that use a single (0.9 mg) vial for each injection treatment given in 3 therapy cycles at monthly intervals, with clinician modeling replaced by patient manipulation and penile stretching at home, have been proposed. Results appear similar to those of the standard treatment protocol.[220][221](B2)

The efficacy of C histolyticum collagenase intralesional injection therapy has been demonstrated in many studies.[212][213][215][222][223][224][225][226][227] Overall, three-quarters of the men treated with intralesional collagenase injections can expect at least a 25% improvement in their penile curvature, with an average improvement of 34%.[212][226] A good responder typically observes a reduction in curvature of about 15°/34% (baseline angulation: 30° to 60°) or 25.5°/23% (baseline angulation: 61° to 90°).[140][226](A1)

The most significant predictor of success in collagenase therapy is the baseline degree of curvature, with the highest percentage benefit observed in patients with a curvature of 60° or more.[215] Good erectile function, lack of plaque calcifications, and stable disease over 2 years are good predictors of favorable outcomes.

C histolyticum intralesional collagenase therapy for Peyronie disease provides overall patient satisfaction rates of about 50% to 67% 1 year after treatment.[228] Longer-term satisfaction is somewhat less, at 42.5%.[228] Recently, several studies have examined the use of C histolyticum intralesional injections during the acute phase of the disease, and they have all shown good efficacy.[229][230][231][232][233][234] The use of collagenase penile injections is not a contraindication to surgical correction later if the final results after intralesional therapy are not satisfactory.[235][236]

Combining collagenase injections with mechanical therapies such as vacuum erection devices or penile traction seems reasonable, is recommended by some experts, and has shown some benefits, but definitive studies are lacking.[141][237][238][239][240][241] A 2019 study showed the potential for combining C histolyticum collagenase intralesional injections with traction therapy.[239] The combined treatment group demonstrated substantial improvement in curvature of 49% (33.8°) and additional penile length of 1.9 cm compared to the collagenase therapy-only group, which had a 31% (20.3°) reduction in curvature but no benefit in penile length.[239] Adding a phosphodiesterase inhibitor has also shown some additional benefits.[180](B3)

Negative predictive factors of collagenase therapy include: [206][226][242][243](A1)

  • An hourglass deformity
  • Baseline penile shaft indentation or narrowing
  • Erectile dysfunction
  • Failure to receive all 4 cycles of therapy
  • Hinge effect
  • Initial curvature >60°
  • Less than 2 years duration
  • Penile buckling
  • Peyronie plaque calcifications

The AUA and CUA guidelines give C histolyticum collagenase injection therapy a moderate recommendation based on grade B (moderate) evidence, and it is approved by the European Medicines Agency and EAU.[60][113][114][244] However, despite its recognized efficacy and guideline recommendations, C histolyticum collagenase may not be available in the European Union, Belgium, Austria, Australia, Canada, or many Asian markets due to its high cost, low utilization, poor demand, and insurance or government reimbursement issues.[245]

Hyaluronic acid: a naturally occurring, non-sulfated glycosaminoglycan normally found in the skin and many other bodily tissues, including the corpora cavernosa and tunica albuginea.[246] Hyaluronic acid acts as an anti-inflammatory agent by modulating inflammatory cell activation and reducing fibroblastic activity, which reduces scarring and fibrosis.[247] In several studies, hyaluronic acid intralesional injections have shown an overall curvature improvement of 5° to 10° but used different dosages, protocols, and durations of therapy.[248][249][250][251][252][253][254] Supplemental oral hyaluronic acid and intralesional injections were more beneficial than plaque injections alone.[253] Hyaluronic acid intralesional therapy may be most beneficial in the acute phase of Peyronie disease.[140](A1)

The most recent systematic review and meta-analysis concluded that hyaluronic acid intralesional therapy provided good overall results, but the quality of the available studies was highly variable, and the available data are quite limited.[255] The AUA guidelines do not mention hyaluronic acid therapy. At this time, it is recommended only for use in clinical trials.[114](A1)

Interferon alpha-2b: injection therapy has shown reasonably good evidence of efficacy in Peyronie disease but in smaller studies compared to C histolyticum collagenase intralesional treatment.[139][256][257][258][259][260][261] The suggested administration protocol is (5×106 units of interferon alpha-2b in 10 mL of normal saline every 2 weeks over 3 months, totaling 6 treatments. (A1)

Interferon alpha-2b reduces fibroblast proliferation, resulting in decreased collagen production, and stimulates collagenase activity.[60][262] Overall improvement in penile curvature is reported at 25% to 30%, with a 50% reduction in plaque size and less pain.[256][257][263] Adverse effects include joint pain and muscle aches with fevers and mild flu-like symptoms commonly observed.[60][257] The AUA guidelines give interferon alpha-2b intralesional injections a moderate recommendation.[60] The EAU and CUA also approve it.[113][114] Despite its efficacy and safety, it is not widely used, most likely due to cost, availability, lack of familiarity, and adverse effects.[114][247][264](A1)

Verapamil: intralesional injections for Peyronie disease appear to offer relatively modest benefits regarding curvature but provide good pain control.[60] The rationale for verapamil therapy is evidence that it inhibits the formation of fibroblasts, alters their metabolic pathways, blocks extracellular matrix production, and increases the activity of collagenase and anti-TGF-ß.[265][266] Although most studies show some modest overall benefit, results are conflicting, with the largest randomized placebo-controlled trial showing no improvement over placebo.[133][140][266][267][268] (A1)

Overall, verapamil intralesional therapy results appear inferior to C histolyticum collagenase, hyaluronic acid, or interferon alpha-2b injections.[139][259] Pain (10%-15%) and bruising (15%-25%) are the most commonly reported adverse effects. (A1)

Many published studies with verapamil injections are poorly designed, with conflicting results, highly varying dosage schedules, no standardized injection protocol, different injected medication concentrations, and a lack of statistical comparisons to the control groups.[60] A randomized clinical trial comparing intralesional injections of C histolyticum collagenase to verapamil injections found the collagenase significantly superior clinically.[269] Verapamil injection therapy for Peyronie disease is permitted under the AUA, CUA, EAU, and ICSM guidelines, which give it a weak, conditional recommendation.[60][113][114][133][174](A1)

Penile traction: Penile traction therapy appears reasonably effective in reducing curvature but does not enhance the girth of the penis. The rationale is that slow continuous stretching of fibrous tissue can result in additional fiber length, changes in the extracellular matrix, boosted mechanotransduction, and tissue remodeling from upregulated collagenase and metalloproteinase activity, as successfully used in Dupuytren contractures, a related disorder involving abnormal collagen deposition resulting in fibrous shrinkage and loss of elasticity.[237][270][271][272][273][274] If unsuccessful, other treatment modalities are still available.

Most studies showed a reasonable mean improvement in penile curvature of about 33% (20% to 50%) and a modest benefit in penile length.[140][237][275][276][277][278][279][280][281] Traction therapy can be used in the acute or chronic phase of the disorder but is probably most helpful when used early.[237] Substantial patient compliance is required for it to be effective.[140] About half of the patients using these devices report difficulty keeping the traction unit in place, and about 30% also indicate discomfort. As a result, some clinicians recommend wearing the device overnight. An athletic supporter may help hold the traction device and minimize pain or discomfort in some patients.(A1)

There is no standardized protocol for traction therapy, no specific device is recommended, and no guide to the strength of the stretching force or optimal daily duration. However, a minimum of 30 to 90 minutes daily has been suggested, with some protocols going up to 8 hours.[275][278] Shorter durations of continuous traction are associated with better patient compliance. The total duration of therapy is typically at least 3 months, but it may be used in the disease's acute and chronic phases.[140][275] 

Among all the conservative treatments for Peyronie disease, only penile traction therapy has demonstrated statistically significant benefits in penile length, curvature, and successful sexual intercourse, as reported by patients.[282] No significant adverse events have been reported.[283]

The most recent systemic review and meta-analysis on penile traction therapy for Peyronie disease concluded that this treatment can be a safe and effective option for men with Peyronie disease to reduce penile curvature. However, the review recommended further research with longer follow-up periods.[277] The European Society for Sexual Medicine considers penile traction therapy a valid treatment option for Peyronie disease, although they find that there is insufficient evidence to justify a definitive recommendation.[284] The CUA, EAU, and ICSM guidelines allow mechanical traction therapy, especially in combination with other treatment modalities.[113][114][133][174](A1)

The AUA guidelines do not offer any opinion or recommendation on penile traction therapy, citing the need for more evidence, but the more recent AUA Core Curriculum on Peyronie disease states that the overall consensus from additional, newer studies has suggested a modest benefit in curvature and length from traction.[60] Given the available evidence, penile traction appears to be a reasonable clinical trial option before considering more invasive surgical interventions, and it is best used as part of a multimodal treatment program.

Topical verapamil: Topical verapamil has been studied with conflicting results. In a study, topical verapamil failed to penetrate the tunica albuginea.[285] However, a double-blinded study involving 18 men with Peyronie disease compared topical verapamil to placebo and noted resolution of pain in 88% and a decrease of penile curvature in 61% after 3 months.[286] Unfortunately, no actual measurements were taken for an objective comparison.[286] Other studies have suggested a possible benefit, but the overall evidence is too scant, with too few participants to be conclusive.[286](B3)

Adverse effects are minimal, with mild skin irritation, erythema, and pruritus reported infrequently. The AUA and CUA guidelines do not currently recommend topical verapamil, citing the need for more studies and evidence, but it is allowed by the EAU and ICSM.[60][113][114][133][174](B3)

Vacuum erection devices: Vacuum erection devices have shown a comparable benefit to traction therapy, but their application, duration, and usage have not been standardized.[237][287][288][289] The rationale for vacuum erection devices use is as follows: [69](B3)

  • Negative pressure from the vacuum and restricted venous outflow dilate the cavernous sinuses and improve corporal oxygenation.[290] 
  • Vacuum erection devices also appear to downregulate TGF-ß1, which blocks fibrosis.[291]
  • Evidence from traction therapy suggests that regular, mechanical penile stretching and manual manipulation may result in plaque micro-fragmentation, allowing the lesion to be remodeled at a reduced angle.[69][281][292]
    • (B3)

Vacuum erection devices have been shown to promote tissue healing after radical prostatectomy surgery, but it remains somewhat unclear if the same benefit occurs in Peyronie disease.[69][290] Most reports showed improvement or stabilization of the curvature in 90% of patients but generally required regular, prolonged use (over 6 hours daily) without using the constriction band and only during the acute phase.[140][237][288][289] However, several studies reported good responses after using the device for only 10 minutes twice daily.[288][289] When combined with other treatment modalities, the AUA and EAU guidelines give vacuum therapy a weak recommendation.[60][113][114][133][140][133][174][140](B3)

Summary of Nonsurgical Treatment 

There is a significant lack of large-scale, well-designed studies supporting nonsurgical therapy for Peyronie disease, despite high patient demand for such treatments. The best available data suggest the following:

  • Potassium para-aminobenzoate (Potaba), vitamin E, carnitine, arginine, tamoxifen, procarbazine, omega-3 fatty acids, botulinum toxin injections, intralesional corticosteroids, radiation therapy, and iontophoresis are not recommended.
  • Among oral therapies, phosphodiesterase type 5 inhibitors (tadalafil 5 mg daily, possibly with a statin), combination antioxidants, pentoxifylline, and coenzyme Q10 offer the best evidence of possible efficacy.
  • Penile traction and vacuum erection devices may be used in both the acute and chronic phases of the disease but are most effective when used early.
  • Intralesional injection therapy with C histolyticum collagenase is approved by the FDA for use in stable or chronic phases of Peyronie disease. This therapy is considered reasonably effective, safe, and practical. Interferon alpha-2b may also be used for intralesional injection therapy.
  • A recent comprehensive review of the available evidence determined that the best nonsurgical therapies are intralesional injections of collagenase (or interferon-alpha-2b) and penile traction devices used alone or together.[141][180]
  • Multimodality treatment has shown evidence of improved efficacy; therefore, combination and multimodal therapy should be considered.[141][152][180][238][293][294][295][296][297] The optimal multimodal combination therapy has not yet been reliably identified.[297]
    • (B2)

Surgical Management

Surgery is the durable and effective treatment for symptomatic Peyronie disease, particularly when severe enough to prevent intercourse and where less invasive therapies have failed.[56] Surgery is not recommended during the acute phase as the penile curvature and deformities must first be stable and unchanged for at least 3 months, although many surgeons prefer to wait at least 6 to 12 months.[56] (B3)

The goal of surgical correction is to achieve a functionally straight penis suitable for sexual intercourse. Patients should clearly understand that although the penis is straighter, it may appear shorter, and results and ultimate patient satisfaction cannot be guaranteed.[60][112][298] Preoperative measurement and documentation of penile length are recommended. The expert consensus opinion is that a penis is considered functionally straight if the remaining curvature after surgery is less than 20°.[133] Surgery to correct small curvatures or defects solely for cosmetic reasons in an otherwise fully functional (capable of intercourse, no erectile dysfunction) penis is not generally recommended.(B3)

Indications for surgical therapy of Peyronie disease include a deformity that impairs satisfactory sexual relations, stable deformity without pain for at least 3 months (some surgeons recommend 12 months or longer), extensive plaque calcification, patient desire for more definitive treatment, and failed nonsurgical therapy.[56][60][114] Procedure decision-making should include consideration of the nature and location of the Peyronie lesion, magnitude of penile deformity, baseline erection function, penile dimensions, surgeon's experience, and patient preference.[299](B3)

Surgical options include penile plication, plaque incision or excision with a graft, or penile prosthesis placement.[300] In general, penile plication is indicated for curvatures <60°, minimal deformities, and good erectile function. Plaque incision or excision with grafting procedures are generally used for curvatures >60° or significant deformities in patients with good erections. Patients with substantial Peyronie disease curvatures and erectile dysfunction are typically best served by penile prosthesis implantation. 

Surgical procedures are briefly described below:

Penile plication (tunica shortening): This surgery is optimal for patients with good preoperative penile rigidity and erection with or without pharmacotherapy (phosphodiesterase type 5 inhibitors, intracavernosal injections), adequate penile length for satisfactory intercourse (loosely defined as 13 cm or more), an uncomplicated curvature of less than 60°, and do not have a significant hinge defect, buckling, or hourglass deformity.

These procedures are sometimes described as penile shortening surgeries, as they reduce the length of the contralateral side of the penis. More complex curvatures and defects may also be managed with penile plication surgery but may require more extensive surgery and a larger number of stitches.[301] Overall, more than 85% of patients undergoing tunical shortening (penile plication) surgery can expect acceptable penile straightening.(B3)

Penile plication procedures start by making a skin incision that exposes the tunica opposite the Peyronie affected (convex) side. The incision can be a small lateral skin incision directly over the area of interest, a midline incision, or a circumcising incision with degloving to expose the tunica. If the Peyronie plaque is in the proximal penile shaft, a penoscrotal incision may be preferred. The intention is to surgically shorten the contralateral tunica so the penis becomes straight. Permanent, nonabsorbable, braided sutures are used, and the knots should be buried. Sutures should be placed no further than 5 mm apart. If necessary, more than one row of plication sutures may be used. There are many variations regarding the precise technique or method used.

Four commonly used techniques are briefly described below:

  • Nesbit procedure: This procedure was the first practical surgical penile plication technique for penile curvature. Nesbit first described the technique in 1965 as a treatment for congenital penile curvature,[302] which later became a mainstay for the surgical correction of Peyronie disease.[303][304] The Nesbit procedure excises an elliptical horizontal wedge of the tunica albuginea from the contralateral (concave) side of the penis opposite the plaque. The penis straightens when this defect is closed.[303][305][306][307][308][309]
  • Yachia Technique: A variation of this technique is to make a vertical incision in the tunica, again on the contralateral side to the Peyronie lesion, and close it transversely (horizontally) in a Heineke-Mikulicz fashion.[221][310][311][312][313][314] The tunica is not excised in this variation.[221][310]
  • Tunica albuginea plication: This procedure starts with 2 parallel incisions (1 to 1.5 cm long), which are made transversely on the contralateral (converse) tunica. The incisions should be no more than 1 cm apart and only deep enough to separate the external longitudinal fibers of the tunica without penetrating or damaging the inner circular fibers. The superficial tunica between the 2 incisions can be removed, and the defect closed with vertical mattress stitches.[298][315][316][317][318][319][320][321][322] A modified technique of extra-tunical grafting combined with tunica albuginea plication has been successfully used for men with Peyronie disease who have corporal indentation without hinge effect or penile buckling.[323]
  • Lue or 16-dot plication technique: In this technique, several stitches can be placed and tied in an interrupted fashion, going across the tunica horizontally, causing it to fold over on itself using a permanent Lembert-type suture.[324][324][325][326][327] As the stitches are tied, the penile length on that side will diminish by the degree of tunical tissue inversion.[324][325][326][327] Multiple parallel plications may be needed for optimal results.[324] The advantage of this technique is that it does not require any incision or excision of the tunica. Still, it may not manage more significant degrees of curvature and other surgeries.
    • (B2)

Penile shortening is reported in more than 40% of men with Peyronie disease who undergo plication procedures. Another 15% experienced a recurrence of their curvature.

Patients can typically resume sexual activity after 4 to 6 weeks of recovery. In addition to the surgeries mentioned, other penile plication procedures include the Giammusso procedure, the Lemberger procedure, the 24-dot procedure, the Essed-Schroeder tunica plication, and the penoscrotal plication procedure.

Potential complications include perceived loss of penile length due to shortening of the long (concave) side of the penis, penile instability, pain, persistence or recurrence of penile curvature, hematoma, urethral injury, and sensory loss from trauma or injury to the neurovascular bundle during dorsal plication procedures.[328] Dorsal neurovascular injuries can be avoided by making tunica incisions and placing sutures further lateral on either side. Erectile dysfunction is rare in patients who did not have erection difficulties preoperatively, especially if the tunica is not fully incised.[309][328] Surgical correction of ventral curvatures can be extremely challenging, as dissection and elevation of the neurovascular bundle or resection of the deep dorsal penile vein may be necessary.

Plaque incision or excision and grafting (tunica lengthening): The indications for this technique include normal preprocedural erectile rigidity, with or without oral pharmacotherapy; complex penile deformity; simple deformity <60°; a large plaque; destabilizing hourglass or hinge effect; and short penile length. For an incisional procedure, a horizontal incision is made on the plaque at the point of maximal curvature on the convex side of the penis. The graft material is then placed within the defect to help lengthen the shorter side of the penis.

An excisional procedure involves removing some or all of the plaque and placing a graft over the resulting defect. Larger excisions tend to have poorer outcomes, so only the minimal amount of tissue necessary is removed as needed for straightening.[329][330] Graft materials include autologous grafts, allografts, and xenografts. Synthetic grafts are no longer recommended due to increased infection risk, contracture of the graft material over time, graft-related inflammation resulting in increased local fibrosis, and possible allergic responses.[331][332][333][334]

All allografts and xenografts are processed sheets of the collagen matrix and are the generally preferred graft material. Synthetic grafts are not recommended.

  • Autografts: Rectus sheath, tunica vaginalis, dermal graft, buccal mucosa, fascia lata, venous patch.
  • Allografts: Pericardium, processed human pericardial grafting, fascia lata process human grafting, 4-layer three-dimensional printed graft.
  • Xenografts: Porcine 4-layer small intestinal submucosa, porcine 1-layer small intestinal submucosa, bovine pericardium, collagen sponge coated with the human coagulation factors fibrinogen and thrombin.
  • A self-adherent collagen-fleece hemostatic patch is also available, which can be used alone or with a penile prosthesis. The patch has a low rate of complications and does not require suturing.[335][336][337]

In general, incisional procedures are preferred.[338][339] Long-term (5-year) patient satisfaction is reported to be at 60%.[340]

Postoperative penile rehabilitation with vacuum erection devices, penile traction, and phosphodiesterase type 5 inhibitors has been suggested to minimize loss of penile length and erectile dysfunction.[341][342] About 50% of patients benefit from or require manual modeling after surgery.[343](B2)

Complications include postoperative erectile dysfunction (up to 50%), infection requiring graft removal, penile hematoma, pain, and recurrence of the curvature.[142] Recurrent curvature is believed to be due to a failure to wait until the Peyronie plaque has fully stabilized or the use of absorbable sutures. Although non-absorbable sutures are typically preferred, long-duration absorbable suture material (polydioxanone) has been used successfully.[303][344]

Up to one-fifth of patients with normal erectile function develop erectile dysfunction after reconstructive surgery for Peyronie disease, and up to 40% may report penile shortening depending on the specific technique used and the graft material selected.[340]

Penile prosthesis placement: This technique can be used with or without modeling, plication, or plaque incision or excision and grafting, and it is most suitable for men with significant erectile dysfunction and significant Peyronie disease, severe deformity refractory to medical therapy, or profound penile instability. Prosthesis placement can be complicated due to Peyronie plaque and associated corporal fibrosis, making dilation of the corpora difficult and increasing the risk of corporal perforation.

Options for penile prostheses include malleable and inflatable devices. Most patients prefer the inflatable prosthesis. Balloon cylinders with limited maximum expansion are recommended. Inflatable devices are far more costly compared to malleable prostheses, which may be a factor in some areas. In many cases, the placement of a prosthesis alone may be sufficient to correct the curvature.[345][346] Repeated activations of an inflatable penile prosthesis tend to gradually decrease any remaining penile curvature over time.[347] 

Establishing whether a 20° penile angle is considered acceptable by the patient preoperatively or if a completely straight penis is desired postoperatively is crucial. Expert consensus suggests that a penis is considered functionally straight if the residual curvature after surgery is less than 20°.[133] 

If there is a remaining curvature of 20° or more after penile prosthesis placement, penile remodeling can be performed.[348] This remodeling process is accomplished by manually bending the penile shaft opposite the direction of the angulation while the prosthesis is inflated.[348] Tubing to the pumping mechanism from the cylinders should be clamped to avoid damaging the mechanism during this procedure. Successful remodeling typically produces a characteristic snap or cracking sound. If this is still insufficient to straighten the penis, a plaque incision or excision with a graft is necessary.[349] 

Overall success, defined as a straight penis, in multiple studies, is reported as 85% to 100%, with patient satisfaction rates generally >70%.[60] Long-term patient satisfaction is reported to be about 60%. This procedure is indicated for the most complex penile deformities and instability, especially in patients with pre-existing erectile dysfunction.[350] Please see StatPearls' companion resource, "Penile Prosthesis Implantation," for more information.[351] 

Experimental Restorative Therapies for Peyronie Disease 

Platelet-rich plasma, stem cell therapy, and laser treatments have been investigated for efficacy in treating Peyronie disease.[201](B3)

Many studies on platelet-rich plasma penile injection therapy have effectively reduced curvature and plaque size.[201][352][353][354][355][356] The combination of percutaneous needle tunneling platelet-rich plasma injections and external vacuum therapy has shown promising results in a prospective, nonrandomized pilot study.[357] In this study, 54 patients with Peyronie disease underwent 6 sessions of percutaneous needle tunneling together with simultaneous platelet-rich plasma injections followed immediately by external vacuum therapy. The treated patients showed significant improvement as the median curvature angle improved from 45° at baseline to 30° after treatment.[357] Another study with an additional 36 patients showed similar results.[358](A1)

Animal studies and early human trials with adipose-derived or mesenchymal stem cells have provided promising results in shrinking plaque size and reducing curvature.[140][201][359][360][361][362] Stem cell therapy with stromal vascular fraction appears particularly promising. Stromal vascular fraction comprises adipose-derived stem cells, endothelial precursor cells, and immune-modulating cells. This cellular mixture synergistically promotes epithelial cellular differentiation and angiogenesis.[362](A1)

Low-intensity laser diode and laser photobiomodulation have also demonstrated potential in limited studies, with one report indicating excellent results in 60% of patients 1 year after treatment.[141][363][364] Despite these promising findings, standardization of the procedure and confirmatory studies are needed before this can be considered for general clinical use.(B3)

Other experimental treatments being evaluated include pirfenidone, a synthetic pyridone drug with anti-inflammatory, antioxidant, and antifibrosis properties used to treat idiopathic pulmonary fibrosis that inhibits TGF-β1 production; nintedanib, a tyrosine kinase inhibitor; IL-13; lysyl oxidase 2; β-thymosins; nitric oxide donors; matrix metalloproteinases or anti-tissue inhibitor of metalloproteinase 1, which reduce collagen synthesis; and antifibrotic agents, such as decorin, follistatin, and Smad 7.[365][366][367] Specific inhibitors such as TGF-β1, platelet-derived growth factors, endothelin-1, and connective tissue growth factors are also being evaluated. 

All of these innovative restorative therapies appear to be safe and promising. However, they are still considered investigational and are therefore not currently recommended by the AUA or the EAU due to insufficient quality clinical evidence of safety and efficacy. The available studies generally have significantly variable protocols, small sample sizes, short follow-up periods, and no control groups.[201][352][354][355] Further research with large, high-quality, randomized controlled trials and adequate long-term follow-up are needed to determine optimal therapies, treatment protocols, effectiveness, therapeutic duration, and safety.[201](A1)

A recent study indicated significant off-label use of these restorative therapies in the United States.[368] Often, patients are not informed about the investigational nature of these treatments or the actual scientific information on their effectiveness.[368] The treatments are not standardized, there is often a lack of scientific data to support claims made to patients, and health insurance does not cover these unapproved therapies, so there is considerable out-of-pocket cost to the patient.[368] Clinicians are involved in about two-thirds of the clinics providing these off-label therapies, and less than 8% are urologists.[368](B3)

Differential Diagnosis

Congenital penile curvature may appear similar to Peyronie disease, but congenital penile curvature is a lifelong condition. The curvature is typically a ventral bowing without acute angulation, with no plaques. True Peyronie disease is acquired and typically dorsal, with acute, sharply angled curvatures being the most common.[51] Indentations, hourglass deformities, and other penile abnormalities are typically absent in congenital curvatures.

Chordee is a ventral penile curvature typically associated with hypospadias and is considered an arrest of normal embryological development. Surgical management is typically performed after 6 months of age.

Management should include intraoperative artificial erection tests at the time of repair to identify the point of maximal curvature and then to perform penile plication. If hypospadias is also present, it should be corrected during the same surgical procedure. Penile fracture involves trauma or contusion resulting in a fracture of the tunica albuginea during sexual intercourse. The typical story involves the sound of a pop with an immediate onset of severe pain and detumescence of the penis. On examination, there is typically penile swelling, ecchymosis, and possible palpable defect in the corpora cavernosa. Diagnosis can be made through physical examination and patient history, along with an MRI of the penis, which demonstrates excellent sensitivity for detecting penile fracture.

Treatment involves penile exploration with a circumferential incision through a subcoronal approach and closure of the cavernosal injury. If there is concern for urethral injury, a cystoscopy should be performed, and any urethral injury should be repaired in the same setting. Penile pain syndrome has a sporadic etiology that could include local conditions such as dermatitis, infection, or ischemia; referred pain from the bladder, prostate, lower back, or hips; neuropathic pain resulting from injury to the dorsal nerve, pudendal nerve, or cauda equina; or psychiatric conditions. Persistent pain can be managed by treating the underlying disease.

Prognosis

The overall prognosis for Peyronie disease is favorable due to the availability of multiple treatment options, both surgical and nonsurgical. For many patients, conservative approaches such as oral medications, intralesional injections, traction therapy, and vacuum erection devices can lead to significant improvement in symptoms, including curvature and pain. In more severe cases, surgical interventions such as penile plication, grafting, or penile prosthesis implantation are effective in restoring function and alleviating deformity. The variety of treatment options allows for personalized care, contributing to positive outcomes for most patients, especially with early diagnosis and intervention.

Complications

Complications include penile ecchymosis, swelling, pain, corporal rupture, erectile dysfunction, and failure to correct the curvature.[369] In addition to all of the other associated problems of pain, embarrassment, and sexual performance issues, men with Peyronie disease suffer an 18% higher frequency of relationship separations per year compared to men of age and socio-economic status without penile disorder.[370]

Surgical complications might consist of infection, urethral injury, penile shortening, pain, hematoma, loss of penile sensation, erectile dysfunction, and recurrence of the curvature. 

Postoperative and Rehabilitation Care

Surgical patients generally have an elastic compression dressing placed immediately after the procedure. This dressing may be removed and replaced with a nonconstricting dressing when appropriate, typically 6 hours postoperatively. The use of an external vacuum erection device several times a day for 6 months is recommended by some, starting 30 days after surgery.[371] 

Patients who received an inflatable penile prosthesis should inflate the device several times daily as soon as this is tolerable, typically 4 to 6 weeks after surgery.

Routine follow-up after surgical reconstruction is recommended every 3 months until the penis is completely healed and stable, typically a year after surgery. Yearly checkups afterward are generally sufficient.

Deterrence and Patient Education

Peyronie disease can be challenging to manage as there are many treatment options, mostly of unproven efficacy. The embarrassing nature of the disorder and the natural reluctance of many patients to seek medical help often results in delayed diagnosis.

Patients should understand that this disorder is likely more prevalent than expected, and numerous options exist to manage it. Intralesional Clostridium histolyticum collagenase intralesional injections are the most effective nonsurgical therapy. Surgical options require stable disease but generally offer excellent results.

Pearls and Other Issues

Summary of Therapies for Peyronie Disease

Conservative treatments:

  • A combination of antioxidants has shown some promising results.[60][69][113][133][139][140][141][142][174][285][286]
  • Coenzyme Q10 may be beneficial and can be used with other treatments. Coenzyme Q10 is inexpensive and unlikely to cause any harm. Although its effectiveness for Peyronie disease is not yet conclusively proven, it offers other potential health benefits.
  • Colchicine is not generally recommended as its efficacy is unclear. 
  • Combination therapy with phosphodiesterase type 5 inhibitors and statins may improve outcomes when used together.
  • Extracorporeal shockwave therapy is beneficial only for pain relief in the acute phase of the disease. Other treatments may be more readily available and cost-effective.
  • Intralesional C histolyticum collagenase injections have the strongest evidence of efficacy among nonsurgical therapies.
  • Intralesional interferon therapy is an effective alternative to C histolyticum collagenase injections and is probably underutilized.
  • Intralesional hyaluronic acid injections appear promising but are recommended only in clinical trials.
  • Intralesional therapy should only be used in the chronic or stable phase of Peyronie disease.
  • Multimodality therapy, including coenzyme Q10, tadalafil, statins, antioxidants, pentoxifylline, and traction therapy, before or with intralesional injections may be worth considering before surgery.
  • Pentoxifylline appears promising, and some data indicate possible efficacy.
  • Tadalafil at a dosage of 5 mg daily (possibly with a statin) and coenzyme Q10 offer the best evidence of efficacy among oral agents. Other medications, such as colchicine, pentoxifylline, potaba, carnitine, arginine, and vitamin E, are not recommended.
  • Topical verapamil has provided conflicting outcomes in studies; therefore, it is not recommended.[285][286]
  • Traction is a promising nonsurgical therapy for Peyronie disease, but no standardized protocol exists. The need for prolonged usage and the lack of standardization protocols limit its use. An athletic supporter and overnight device application may help minimize patient discomfort and device displacement.
  • Traction is possibly most useful as an adjunct to other oral or intralesional therapies.
  • Verapamil gel can be considered where available.

Surgical procedures:

  • Indications for surgery include a lesion that is stable and pain-free for at least 3 months (some prefer to wait at least 1 year), failure of more conservative therapies, sufficient deformity to interfere with intercourse, and calcified Peyronie plaques.
  • Plication procedures are recommended when the penile curvature is <60°, and the patient has a good erectile function.
  • Incisional or excisional procedures with grafting are indicated for patients who are not candidates for plication, such as where the curvature is >60°, complex regulations, unstable penile shaft deformities, large Peyronie plaques, or a short penis. The patient should also have good erectile function. 
  • Surgical patients who also have erectile dysfunction are best served with the placement of a penile prosthesis.
  • If an inflatable penile prosthesis is implanted, selecting balloon cylinders with limited or restricted maximal expansion is suggested.
  • Manual remodeling after penile prosthesis may be necessary in some cases.
  • Thinning of the plaque using a dental drill with a carbide burr attachment has been attempted. Although initial results were encouraging, the incidence of penile shortening, plaque recurrence, and return of penile angulation was unacceptable, so the technique has been abandoned.[372]

Enhancing Healthcare Team Outcomes

The extremely embarrassing nature of this disorder is why men rarely discuss this issue with their primary care providers unless prompted. Nevertheless, primary care providers are vital in identifying patients potentially suffering from Peyronie disease. The sensitive nature of the problem requires delicate handling by primary care providers and the other healthcare professionals involved in the patient's care. 

An effective technique is to ask the patient, How is your sex life? Is everything working OK for you? This question should be posed in a conversational tone and in a manner where the intonation suggests no suspicion that there may be a sexual problem. If the patient hesitates or delays in responding positively, it indicates a need for the clinician to gently inquire further, as those with no issues are likely to respond affirmatively right away.

Primary care clinicians must be able to have an open and nonjudgemental discussion with their patients regarding their sexual activity and satisfaction with their sexual ability, as this is often the first opportunity to uncover issues such as Peyronie disease. Primary care clinicians should communicate that penile curvature and Peyronie plaques are treatable conditions, and the affected patients should be referred to a urologist for further treatment. Urologists can provide various solutions, advancing the patient's care toward resolution. Medical professionals must coordinate care and communicate effectively to ensure optimal patient outcomes. 

Effective coordination and communication among medical professionals are essential to ensure optimal patient outcomes. The key lies in the early identification of the patient's problem and timely referral to the appropriate medical specialist.

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